Fibroblast growth factor receptors (FGFRs) are receptor-type protein tyrosine kinases (PTK). FGFRs are enzymes that are activated by dimerization caused by the binding of a fibroblast growth factor (FGF), which is a ligand of the kinases, and that phosphorylate various proteins, which are intracellular substrates, and thus relate to proliferation and differentiation of cells. It is known that FGFRs include four subtypes, namely, FGFR1 to FGFR4 [Expert Opinion on Therapeutic Targets, Vol. 6, p. 469 (2002)]. Recently, according to results of the examination of patient specimens, the FGFR3 gene is overexpressed by a chromosome translocation in about 25% of patients having multiple myeloma [Blood, Vol. 92, p. 3025 (1998)]. In addition, the FGF is highly expressed in the bone marrow of patients having multiple myeloma, and thus it is believed that activation of FGFR3 signals occurs in multiple myeloma cells that express, FGFR3 [Blood, Vol. 101, p. 2775 (2003)]. Furthermore, an active mutation of FGFR3 in cell strain and patient specimens of multiple myeloma is known, and it is believed that, by transmitting cell proliferation signals, such a constant-activation causes infinite proliferation of cells, and this is an important cause of multiple myeloma [Blood, Vol. 97 p. 729 (2001)]. Furthermore, overexpression and active mutation of FGF or FGFR have been reported in various types of cancers other than multiple myeloma (for example, pituitary tumor, myeloproliferative disease, renal cancer, urinary bladder cancer, colon cancer, head and neck cancer, skin cancer, stomach cancer, non-Hodgkin's lymphoma, brain tumor, breast cancer, and ovarian cancer) [Expert Opinion on Therapeutic Targets, Vol. 6, p. 469 (2002) and Nature, Vol. 411, p. 355 (2001)]. Accordingly, it is believed that an FGFR inhibitor is useful as a therapeutic agent for various cancers such as multiple myeloma.
Aurora kinases are serine/threonine kinases that are activated during the cell division phase (G2/M phase) and it has been reported that Aurora kinases are involved in centrosome duplication, chromosome separation, cytokinesis and the like. It is known that Aurora kinases include three subtypes, namely, Aurora A, Aurora B, and Aurora C. Among these, Aurora A is present on chromosome 20q13 whose amplification has been reported in various types of cancers. Overexpression of Aurora A has been frequently observed in breast cancer, colon cancer, urinary bladder cancer, pancreatic cancer, stomach cancer, ovarian cancer, esophageal cancer, liver cancer and the like, and the correlation between Aurora A and the degree of malignancy or the prognosis of the diseases has also been reported [Trends in Cell Biology, Vol. 9, p. 454 (1999); British Journal of Cancer, Vol. 84, p. 824 (2001); Journal of National Cancer Institute, Vol. 94, p. 1320 (2002); Clinical Cancer Research, Vol. 9, p. 1420 (2003); Clinical Cancer Research, Vol. 11, p. 1827 (2005); and Clinical Cancer Research, Vol. 10, p. 2065 (2004)]. It has been reported that Aurora B is also overexpressed together with Aurora A in clinical specimens of breast cancer and colon cancer [Oncogene, Vol. 14, p. 2195 (1997); and EMBO Journal, Vol. 17, p. 3052 (1998)]. It is believed that such an abnormal activity of mitotic kinase is one of the causes of chromosome instability, which is a characteristic of many cancer cells. Accordingly, it is believed that an Aurora inhibitor is useful as a therapeutic agent for various cancers such as colon cancer.
Fms-like tyrosine kinase 3 (hereinafter referred to as Flt-3) is a receptor-type protein tyrosine kinase (PTK) belonging to a platelet-derived growth factor receptor (PDGFR) family. Flt-3 is an enzyme that is activated by dimerization caused by the binding of an Flt-3 ligand, which is a ligand of the kinase, and that phosphorylates various proteins, which are intracellular substrates, and thus relates to proliferation and differentiation of cells. It is known that, Flt-3 is particularly expressed in hematopoietic stem cells, and Flt-3 or Flk-2 (Fetai liver kinase-2) plays an important role in proliferation thereof [Cell, Vol. 65, p. 1143 (1991)]. Recently, results of examination of specimens from leukemia patients showed that activation of Flt-3 occurs without ligand binding to Flt-3 by a mutation caused by inserting a repetitive sequence of tyrosine residue in the juxtamembrane domain of Flt-3 (internal tandem duplication (ITD)) [Leukemia, Vol. 11, p. 1447 (1997)]. It has also been reported that a similar activation of Flt-3 is caused by a mutations including elongation or shortening of the amino-acid sequence in the juxtamembrane domain of Flt-3 [Blood, Vol. 96, p. 3907 (2000)]. In addition, it has been reported that Flt-3 is activated by a point mutation of an amino acid in the kinase domain of Flt-3 [Blood, Vol. 97, p. 2434 (2001)]. It is believed that such a constitutive activation based on these Flt-3 mutations causes infinite proliferation of cells by transmitting cell proliferation signals and therefore is an important cause of leukemia. Accordingly, it is believed that an Flt-3 inhibitor is useful as a therapeutic agent for various cancers such as leukemia. Drugs such as SU11248, CHIR-258, CT53518, CEP-701, and PKC412 have been reported as drugs that act on Flt-3. It is known that these drugs exhibit an antitumor activity in leukemia-transplant mice [Blood, Vol. 101, p. 3597 (2003); Clinical Cancer Research, Vol. 11, p. 5281 (2005); Cancer Cell, Vol. 1, p. 421 (2002); Blood, Vol. 99, p. 3885 (2002); and Cancer Cell, Vol. 1, p. 433 (2002)].
As described above, inhibitors against a kinase relating to proliferation, differentiation or malignant alteration of cancer cells have attracted attention as novel antitumor agents. For example, Imatinib that selectively inhibits Abl kinase is clinically used as a drug that has low toxicity and a high clinical effect to chronic leukemia patients [New England Journal of Medicine], Vol. 345, p. 645 (2002)]. Drugs such as PD173074, PKC412, BIBF1000, CHIR-258, and SU5402 have been reported to act on FGFR. It is known that these drugs exhibit an antitumor activity in several evaluation models [Blood, Vol. 103, p. 3521 (2004); Leukemia, Vol. 18, p. 962 (2004); Oncogene, Vol. 24, p. 8259 (2005); Blood, Vol. 107, p. 2079 (2006); Blood, Vol. 105, p. 2941 (2005); and Clinical cancer research, Vol. 11, p. 2702 (2005)]. Examples of known drugs that inhibit Aurora kinases include Hesperadin [The Journal of Cell Biology, Vol. 161, p. 281 (2003); US2003/0069299], ZM447439 [The Journal of Cell Biology, Vol. 161, p. 267 (2003); WO01/21596], PHA-680632 [Journal of Medicinal Chemistry, Vol. 48, p. 3080 (2005); WO02/12242], AZD1152 [Journal of Medicinal Chemistry, Vol. 49, p. 955 (2006), Bioorganic & Medicinal Chemistry Letters, Vol. 16, p. 1320 (2006); WO04/058781], JNJ-7706621 [Journal of Medicinal Chemistry, Vol. 48, p. 4208 (2005)], VX-680 [Current Topics in Medicinal Chemistry, Vol. 5, p. 199 (2005); and Expert Opinion on Therapeutic Patents, Vol. 15, p. 1169 (2005)], or the like. It has been reported that VX-680 exhibits an antitumor activity in human-tumor-transplant mouse and rat models [Nature Review. Cancer, Vol. 4, p. 927 (2004); and Nature Medicine, Vol. 3, p. 262 (2004)]. It has been reported that JNJ-7706621 exhibits an antitumor activity in human-tumor-transplant mouse models [Cancer Research, Vol. 65, p. 9038 (2005)]. However, drugs that simultaneously inhibit several kinases having an important role in cancers and exhibit an antitumor activity by mechanisms based on the inhibition of the function of the kinases have not been reported. Accordingly, drugs that not only inhibit a respective kinase but also target several kinases simultaneously are expected to be useful as novel antitumor agents.
Isoindolinone derivatives having an inhibitory activity against vascular endothelial growth factor receptor (VEGFR2)/kinase insert domain receptor (KDR) are known (Patent Documents 1 to 3 and Non-Patent Document 1).
Phthalimide derivatives having an inhibitory activity against AKT, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), p70 ribosomal S6 kinase (p70S6K), and p160-Rho-associated coiled-coil-containing protein kinase (ROCK) are known (Patent Document 4).
Isoindolinone derivatives having an inhibitory activity against mitogen-activated protein kinase kinase (MEK) are known (Patent Document 5).
Patent Document 1: WO 04/108672
Patent Document 2: U.S. Patent Application Publication 2005/0026976
Patent Document 3: WO 04/021532
Patent Document 4: WO 05/039564
Patent Document 5: WO 05/051300
Non-Patent Document 1: “Bioorganic & Medicinal Chemistry Letters”, Vol. 14, p. 4505, 2004